Biomedical Engineering Reference
In-Depth Information
envisioned for attaching drug molecules of choice. The functionalization of this
dendrimer with
t
-butyl carbazate or glutamic acid derivative
10
was not successful
as degradation of the dendrimer was occurring during the reaction. For further
insight with respect to the degradation pathway, the authors designed dendrimer
11
and further functionalized with aspartic acid chain ends. Scaffold
11
was used
since the progress of its reaction was monitored by MALDI-TOF over to PEGylated
dendrimer
9
(Scheme 10.6 ).
Due to degradation side reaction, only a small amount of the target moiety was
only reported, thereby leading to the appearance of lower molecular weight prod-
ucts as a result of intramolecular cyclization reactions as proposed in Scheme
10.7. This kind of cyclization reactions with benzyl ester-protected aspartic acid
residues are reported in the literature [49]. Earlier, pentachlorophenol (PCP) has
been used to decrease the formation of the aminosuccinyl by-product by inhibit-
ing amide deprotonation. While, in buffered conditions, the primary amines are
favorable to react with PNP carbonates and other electrophiles. It has been
reported that the use of PCP was benefi cial since it allows the functionalization
of the carboxylic acid side chains of dendrimer
9
with protected nucleophile
10
to give dendrimer
12
(Scheme 10.6). Furthermore, DOX hydrazone conjugate
14
was synthesized by removing Boc groups from the hydrazide linkers in
12
and
by condensation of the resulting amines with the ketone group of DOX
13
(Scheme 10.6). The degradation of polyester architecture was evaluated in physi-
ological conditions. Therefore,
12
was incubated in phosphate-buffered saline
buffer at 37 °C and the molecular weight with time was monitored by SEC. Due
to rapid degradation, alternative dendrimer scaffolds based on robust polyamide
core were explored.
10.3.1.1
Polylysine - Core Biodegradable Dendrimer Prodrug
Compared to polyester dendrimers, polyamide dendrimers are less susceptible to
hydrolysis; however, due to increased stability, it may affect
in vivo
pharmacokinet-
ics Recently, Fox
et al.
reported PEGylated polylysine consisting of camptothecin
with 100% survival in transgenic mice using HT-29 human colon carcinoma for
a period of 70 days (Scheme 10.8) [50]. It is to be noted that the very slow or
incomplete degradation of the polymeric carrier's by-product may lead to toxicity
[51] . Delivery of DOX using polylysine carrier is reported [50] in the form of den-
drimer
18
having protected hydrazide molecules (Scheme 10.8).
As shown in Scheme 10.8, lysine dendrimer
15
was used as the starting mate-
rial. Its peripheral amines were acylated with PNP-Asp(Bn)Boc to afford den-
drimer
17
. The authors pointed out that the PCP additive is critical for conjugating
aspartic acid to G2 lysine periphery; if not, a fi ve-membered amino succinyl by-
product may be formed via amidolysis of the benzyl ester-protected side chain. By
deprotecting of amino groups of the aspartate and PEGylation with PEG-
p
- nitro-
phenyl, carbonate yields
18
. However, coupling
t
-butyl carbazate to the deprotected
side chain of carboxylic acid terminal moieties (
19
) leads to degradation by-
products such as
20
(Scheme 10.8). Furthermore, the drug was conjugated using
PEGylated ester amide dendrimers (
25
-
27
) as represented in Scheme 10.10.
